Baseline Characteristics and Interim Safety in RESPOND: A Phase 4 Study in Children with Spinal Muscular Atrophy (SMA) Treated With Nusinersen After Onasemnogene Abeparvovec
Nancy Kuntz1, Julie Parsons2, John F. Brandsema3, Crystal Proud4, Richard Finkel5, Kathryn Swoboda6, Ricardo Masson7, Yingying Liu8, Corinne Makepeace8, Angela Paradis8, Zdenek Berger8, Kathleen Somera-Molina8
1Ann & Robert H Lurie Children'S Hospital of Chicago, 2Children's Hospital Colorado, 3Children’s Hospital of Philadelphia, 4Children's Hospital of The King's Daughters, 5St. Jude Children's Research Hospital, 6Massachusetts General Hospital, 7Fondazione IRCCS Istituto Neurologico Carlo Besta, 8Biogen
Objective:
To provide baseline characteristics and interim safety findings in RESPOND (NCT04488133), a single-arm study evaluating nusinersen in children with SMA previously treated with onasemnogene abeparvovec (OA).
Background:
OA is an adeno-associated viral (AAV) vector gene therapy for SMA in children age <2 years. Animal models and limited human postmortem studies have demonstrated incomplete transduction of motor neurons by the AAV9 vector. Nusinersen has potential to increase SMN protein in untransduced motor neurons, which may provide additional clinical benefit to SMA patients.
Design/Methods:
In RESPOND, children ≤36 months old with SMA and ≥1 SMN2 copy who are nusinersen-naïve and have suboptimal clinical status following OA administered ≥2 months previously, receive the approved 12-mg nusinersen regimen: 4 loading doses followed by maintenance doses every 4 months. Suboptimal clinical status (investigator-determined) includes ≥1 of these domains: motor function, respiratory support, swallowing/feeding ability, other. Recruitment is ongoing.
Results:
As of 15 August 2022, 34 children were enrolled and dosed. Median time from OA treatment to first nusinersen dose was 6.9 (range: 3–31) months. At baseline, 28/34 children demonstrated suboptimal clinical status in ≥2 domains after OA treatment; motor function (n=33) and respiratory function (n=22) were most common. Baseline mean±SD HINE-2 total score was 6.7±5.7 (n=33). Median duration on nusinersen was 183 (range: 1–540) days. Thirty of 34 participants had 2 SMN2 copies. AEs were typical of SMA; the most common were upper respiratory tract infection (n=6) and viral upper respiratory tract infection (n=5). Two participants had mild proteinuria considered nusinersen-related, which resolved. Nine participants had serious AEs; all were considered unrelated to nusinersen and resolved. No deaths or post-lumbar puncture syndrome events occurred. Additional data will be presented.
Conclusions:
In RESPOND, the majority of enrolled children had suboptimal clinical status in ≥2 domains at baseline after OA treatment. Interim safety findings were overall consistent with nusinersen’s safety profile.